1. Field of the Invention
This invention relates to use, preparation, and pharmaceutical compositions of carbazole and cyclopentaindole derivatives, used in the treatment and/or prevention of Hepatitis C viral infection.
2. Related Background Art
Hepatitis C is a common viral infection that can lead to chronic Hepatitis, cirrhosis, liver failure, and hepatocellular carcinoma. Infection with the Hepatitis C virus (HCV) leads to chronic Hepatitis in at least 85% of cases, is the leading reason for liver transplantation, and is responsible for at least 10,000 deaths annually in the United States (Hepatology, 1997, 26 (Suppl. 1), 2S-10S).
The Hepatitis C virus is a member of the Flaviviridae family, and the genome of HCV is a single-stranded linear RNA of positive sense (Hepatology, 1997, 26 (Suppl. 1), 11S-14S). HCV displays extensive genetic heterogeneity; at least 6 genotypes and more than 50 subtypes have been identified.
There is no effective vaccine to prevent HCV infection. The only therapy currently available is treatment with interferon-α (INF-α or combination therapy of INF-α with the nucleoside analog ribavirin (Antiviral Chemistry and Chemotherapy, 1997, 8, 281-301). However, only about 40% of treated patients develop a sustained response, so there is a need for more effective anti-HCV therapeutic agents.
The HCV genome contains a number of non-structural proteins: NS2, NS3, NS4A, NS4B, NS5A, and NS5B (J. General Virology, 2000, 81, 1631-1648). NS5B is an RNA-dependent RNA polymerase which is essential for viral replication, and therefore, the inhibition of NS5B is a suitable target for the development of therapeutic agents.
U.S. Pat. Nos. 5,830,911; 5,776,967; 4,810,699 and 4,782,076 disclose the use of certain compounds of the general formula below (where R11=H, Y=CH2 and m=1 or an oxygen atom) as analgesics, anti-inflammatories and as inhibitors of COX-2.

These compounds are also used for treating lymphocytic leukemia in WO 2000002555. Certain compounds (where Y=CH2R, m=1 and R11=substituted benzyl) are disclosed as inhibitors of leukotriene synthesis and as prostaglandin antagonists in EP-239306, EP-300676, EP-310179, CA 1299577, EP-468785 and as a medicament for limiting cyclosporin-induced nephrotoxicity in EP307077.
Cyclopentaindole derivatives (where m=0, Y=a bond) are described as useful prostaglandin antagonists in WO200208186. Other compounds (where R11=H, m=1, Y=a bond and R2=H) are described as useful antidepressants in DE-2263682 and as useful anti-diabetics in DE-2226702.
None of these prior art references discloses or suggests the use of carbazole and cyclopentaindole derivatives for the treatment and/or prevention of HCV. As noted above, there is a continuing desire for anti-HCV therapeutic agents.